Macrophages are essential elements of the immune system that orchestrate activation and down-regulation of inflammatory reactions, tissue remodelling, healing processes and tissue homeostasis. Macrophages have to respond to complex signals specific for homeostatic or pathologic conditions. To retain sufficient accuracy of reaction, macrophages make use of the co-operative action of multiple extracellular factors that may amplify required activities and suppress undesired ones. This co-operativity is based on complex branching signalling networks coupled to positive and negative feedback loops; ligand uptake by scavenger receptors; intracellular sorting and multiple secretory pathways. Deregulation of co-operativity leads to pathological situations such as chronic inflammation, allergy, tumour initiation, and progression. The complexity of the system makes it impossible to assess the impact of every particular molecular event using classical molecular biological methodology. Mathematical modelling of signalling and membrane trafficking pathways using frameworks of differential equations will allow qualitative and quantitative description of macrophage behaviour in conditions simulating physiological situations. Although model construction requires large amounts of quantitative experimental data, the analysis of the model using mathematical methods enables the identification of the elements critical for the system. Established models may be used to simulate behaviour of macrophages under different conditions and to predict their reactions in vivo. Identified critical elements of the system will facilitate the isolation of predictive/diagnostic markers as well as potential therapeutic targets.